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Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy.

Authors :
Gozzelino L
Kochlamazashvili G
Baldassari S
Mackintosh AI
Licchetta L
Iovino E
Liu YC
Bennett CA
Bennett MF
Damiano JA
Zsurka G
Marconi C
Giangregorio T
Magini P
Kuijpers M
Maritzen T
Norata GD
Baulac S
Canafoglia L
Seri M
Tinuper P
Scheffer IE
Bahlo M
Berkovic SF
Hildebrand MS
Kunz WS
Giordano L
Bisulli F
Martini M
Haucke V
Hirsch E
Pippucci T
Source :
Brain : a journal of neurology [Brain] 2022 Jul 29; Vol. 145 (7), pp. 2313-2331.
Publication Year :
2022

Abstract

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients' variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.<br /> (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Details

Language :
English
ISSN :
1460-2156
Volume :
145
Issue :
7
Database :
MEDLINE
Journal :
Brain : a journal of neurology
Publication Type :
Academic Journal
Accession number :
35786744
Full Text :
https://doi.org/10.1093/brain/awac082